It is generally recognized that NIDDM is not a single disease, but rather a heterogeneous group of metabolic disorders that share glucose intolerance. The precise metabolic defects are still unknown, and the relative primacy of defective insulin secretion vs. defective insulin action is still controversial Knowledge of the etiology of NIDDM would likely serve to facilitate early diagnosis, treatment, and prevention. This grant seeks to define the etiology of the metabolic defects in NIDDM by clarifying their genetic basis. The focus of this grant is on Ashkenazi Jews, a distinct ethnic group which is genetically, relatively homogeneous. The hypothesis to be tested is that the metabolic defects in NIDDM are the result of a limited number of diabetogenic genes, each with moderate effect, and that the power to detect these genes is greater in a homogeneous population such as the Ashkenazi Jews. NIDDM genes will be identified in this group as follows: 1) Clinical/demographic data, and genomic DNA will be collected on 400 affected Ashkenazi Jewish sib pairs (800 NIDDM subjects), through the Diabetes Clinics of the Haddasah Hospital and of the General Sick Fund of the Histadrut in Israel. Admission criteria includes the requirement that at least one member of an affected pair must have been diagnosed before age 55, to enhance the genetic risk. This population has a relatively high prevalence of NIDDM, and the current gene pool developed from a small initial population about 700 years ago. Furthermore, there is easy access to patients in Israel in a relatively stable population, with similar environmental backgrounds, and where diabetes treatment is concentrated in a limited number of specialized centers; 2). A whole genome search (positional cloning) will be accomplished using a protocol based on multiplex PCR of simple sequence repeat polymorphic markers (SSRPs) and automated DNA fragment analysis. SSRPs will be developed for multiplex PCR with fluorescent labeled primers and automated scoring to assure maximum possible coverage of the human genome with intervals no larger than 10 cM. Data analysis will be conducted using the nonparametric identity by state (IBS) analysis on all affected sib pairs. Any locus which meets the follow-up criteria (nominal p-value less than 0.05), will be subject to follow-up analysis including parametric analyses and typing of flanking markers. (Positive findings in Ashkenazi will be replicated in other racial/ethnic groups.) Through the studies outlined above, he anticipates that within a four year period he will have collected a valuable genetic resource for identification of NIDDM genes and will have identified regions of the genome where diabetogenic genes reside. Defining the nature of these gene defects will enhance efforts toward achieving his long range goal of determining the metabolic basis of NIDDM.